title: Synthesis and biological evaluation of novel delta (δ) opioid receptor ligands with diazatricyclodecane skeletons.
abstract: Considering the interesting pharmacological profile of the delta (δ) selective opioid agonist compound SNC-80, conformationally constrained analogs containing two diazatricyclodecane ring systems in place of dimethylpiperazine core motif were synthesized. The compounds showed subnanomolar or low nanomolar δ opioid receptor binding affinity. Depending upon the substituents on the diazatricyclodecane ring, these compounds displayed varying selectivity for δ opioid receptor over μ and κ receptors. Amongst the novel compounds, 1Aa showed the more interesting biological profile, with higher δ affinity and selectivity compared to SNC-80. The δ receptor agonist profile and antinociceptive activity of 1Aa were confirmed using ex-vivo (isolated mouse vas deferens) and in vivo (tail flick) assays.
authors.affiliation: C.N.R. Istituto di Farmacologia Traslazionale, UOS Cagliari, Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy. Electronic address: giovanni.loriga@ift.cnr.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Loriga
authors.forename: Paolo
authors.initials: P
authors.lastname: Lazzari
authors.forename: Stefania
authors.initials: S
authors.lastname: Ruiu
authors.forename: Giorgio
authors.initials: G
authors.lastname: Marchese
authors.forename: Ilaria
authors.initials: I
authors.lastname: Manca
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Casu
authors.forename: Christian
authors.initials: C
authors.lastname: Dessì
authors.forename: Gérard Aimè
authors.initials: GA
authors.lastname: Pinna
authors.forename: Battistina
authors.initials: B
authors.lastname: Asproni
authors.forename: Gabriele
authors.initials: G
authors.lastname: Murineddu
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D011083:Polycyclic Compounds / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C000589298:4-((10-allyl-9,10-diazatricyclo(4.2.1.12,5)dec-9-yl)-(3-methoxyphenyl)methyl)-N,N-diethylbenzamide; D000700:Analgesics; D008024:Ligands; D011083:Polycyclic Compounds; D017465:Receptors, Opioid, delta
keywords: 2,7-Diazatricyclo[4.4.0.0(3,8)]decane; 9,10-Diazatricyclo[4.2.1.1(2,5)]decane; Antinociceptive activity; Binding assays; δ-Agonist SNC-80; δ-Opioid receptor ligands